There are no generalizable rational treatments for patients with mitochondrial diseases. We propose here to study two new approaches to treat patients with mitochondrial diseases due to mutations in mtDNA. First, we have found that rapamycin (Sirolimus), an FDA-approved drug that induces autophagy, selectively targets mitochondria containing mutated mtDNAs, but not those harboring normal mtDNAs, for autophagic destruction. We will therefore examine the ability of rapamycin to restore mitochondrial function in heteroplasmic cells ("heteroplasmic shifting"), and use biochemical, functional, and microarray-based approaches to determine how mutant mtDNAs and dysfunctional mitochondria are recognized and degraded by the cell's autophagic machinery. Second, we have found that a number of analogs of CoQ and vitamin E developed by Edison Pharmaceuticals can rescue the viability of cells from patients with MELAS ("functional rescue"). We will therefore study Edison compounds in patient cells harboring various pathogenic mtDNA mutations in greater detail, and will also try to determine the mechanism by which these compounds work, using biochemical and genetic approaches. If successful, use of both rapamycin and Edison compounds could be the the basis of the first rational treatments of mtDNA-based OxPhos diseases.